Macromolecules 2010, 43, 7033–7040
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DOI: 10.1021/ma100983p
Reversible Interpolyelectrolyte Shell Cross-Linked Micelles from pH/Salt-Responsive Diblock Copolymers Synthesized via RAFT in Aqueous Solution† Matthew G. Kellum,‡ Adam E. Smith,‡ Stacey Kirkland York,‡ and Charles L. McCormick*,‡,§ ‡ Department of Polymer Science and §Department of Chemistry and Biochemistry, University of Southern Mississippi, Hattiesburg, Mississippi 39406
Received May 11, 2010; Revised Manuscript Received July 15, 2010
ABSTRACT: Herein we report the synthesis and characterization of a series of pH reversible shell crosslinked micelles. A series of novel pH/salt-responsive block copolymers of poly(sodium 2-acrylamido-2methyl-1-propanesulfonate-block-N-acryloyl-L-alanine) (P(AMPS-b-AAL)) were synthesized utilizing aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization. Micellization of P(AMPS-bAAL) is induced by rendering the PAAL block hydrophobic through protonation of the carboxylic acid (pH 1-3). The pH at which micelle formation occurs and the hydrodynamic diameters of the resultant micelles are dictated by block copolymer composition and electrolyte concentration. The anionic PAMPS micelle shells were subsequently cross-linked with a RAFT synthesized cationic homopolymer of either poly(N-[3-(dimethylamino)propyl]acrylamide) (PDMAPA, pKa = 8.5) or poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA, pKa = 7.3). Upon deprotonation of the PAAL block, these cross-linked micelles swell but remain stable and intact. Significantly, the reversibility of the cross-linking was determined to be tunable by utilizing the different cationic homopolymers for cross-linking. This was demonstrated by increasing the pH above the pKa of the cationic homopolymer cross-linker, resulting in deprotonation of the cationic cross-linker and dissociation of the cross-linked micelles.
Introduction Recently, a great deal of interest has been focused on the synthesis of well-defined, water-soluble block copolymers capable of self-assembling in response to external stimuli. These polymers typically contain a permanently hydrophilic block and a responsive block which upon application of an external stimulus (i.e., temperature, pH, or electrolyte concentration) is rendered hydrophobic. Upon conversion to a hydrophilic-hydrophobic copolymer, self-assembly into higher order structures such as micelles is possible.1-6 The ability to control the assembly/disassembly process through environmental cues makes these materials attractive candidates for controlled release applications in which hydrophobic agents are loaded into the core of the structure and subsequently carried until exposed to an external stimulus.7-21 However, practical applications remain limited due to dilution effects, specifically the disassembly of micelles into unimers as the concentration of polymer falls below the critical micelle concentration. In order to circumvent dilution effects, researchers have developed a number of methods to either permanently or reversibly cross-link the micelles. In the seminal report on covalent shell crosslinked (SCL) micelles, Wooley and co-workers utilized free radical chemistry to cross-link pendent vinyl groups within the shells of micellar assemblies.22 Subsequently, numerous shell cross-linking methods have been developed including UV-induced coupling of cinnamoyl groups,23-25 carbodiimide coupling,7,26,27 quaternization of amines using 1,2-bis(2-iodoethoxy)ethane,28-30 cross-linking pendent hydroxyls with divinyl sulfone,31,32 click chemistry,33 and multivalent Au ligation through in situ reduction.34,35 Recently, our group reported the facile formation of SCL micelles and reversible SCL micelles utilizing a reaction between activated † Paper number 148 in a series on Water-Soluble Polymers. *Corresponding author. E-mail:
[email protected].
r 2010 American Chemical Society
esters and diamines.36-39 Briefly, a disulfide-containing diamine (cysteamine) was reacted with activated esters within a micellar shell. By introducing reducing/oxidizing agents, the cross-links could be formed or broken. Since initial reports on shell crosslinking, a number of alternate cross-linking procedures have been introduced and are described in a review by Armes et al.40 Although advantageous, many of these cross-linking techniques are limited by low reaction efficiency, reagent insolubility, irreversibility, and extensive purification techniques to remove small molecule byproducts. An alternate approach involves the careful design of polymeric micelles containing charged segments for complexation with oppositely charged polymers to form interpolyelectrolyte complexed micelles.41 This technique provides many advantages over traditional cross-linking reactions including near instantaneous cross-linking, solvent selection (aqueous environment), lack of byproducts, and reversibility in the presence of added electrolytes. Previously, our group designed both temperature3,42 and pH43 responsive systems capable of forming these interpolyelectrolyte complex micelles and demonstrated their reversibility with added electrolytes. Although reversible, a high salt concentration (>1 M) is required to disrupt these cross-linked micelles rendering them impractical for use as drug delivery vehicles. In order to circumvent these deficiencies, we have designed a novel micelle-forming, pH-responsive block copolymer system cross-linked via interpolyelectrolyte complexation in which the cross-linking is reversibly induced by a change in solution pH. Even more importantly, we demonstrate that the extent of pH-induced dissociation of shell cross-linked micelles can be altered by simply changing the cationic homopolymer used to form the interpolyelectrolyte complex. Herein, we report the strategic design of pH-responsive, micelle-forming block copolymers which contain an anionically charged corona and an insoluble protonated core at low pH. The Published on Web 07/30/2010
pubs.acs.org/Macromolecules
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Macromolecules, Vol. 43, No. 17, 2010
block copolymers which comprise the micelles were synthesized via aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization and consist of a hydrophilic, anionically charged poly(sodium 2-acrylamido-2-methyl-1-propanesulfonate) (PAMPS) block and a pH-responsive poly(N-acryloyl-L-alanine) (PAAL) block. These block copolymers undergo a reversible unimer-to-micelle transition upon lowering the solution pH. The micelles can be cross-linked via interpolyelectrolyte complexation utilizing the anionic PAMPS shell and a cationic homopolymer, in the current case either protonated poly(N-[3-(dimethylamino)propyl]acrylamide) (PDMAPA) or poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA). The pH reversibility of these systems is demonstrated by increasing the solution pH to deprotonate the polycation cross-linker, resulting in dissociation of the cross-linked micelles to their respective water-soluble unimer components. Experimental Section Materials. All reagents were purchased from Aldrich at the highest purity available and used as received unless otherwise stated. 4-Cyanopentanoic acid dithiobenzoate (CTP) was synthesized according to literature procedures.44 4,40 -Azobis(4-cyanopentanoic acid) (V-501) was donated by Wako Chemicals and was recrystallized twice from methanol before use. DMAPA was purchased from TCI and vacuum-distilled prior to use. AAL was synthesized according to literature procedures.3 The synthesis of poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA) was previously reported.35 Instrumentation. Block copolymers of P(AMPSn-b-AALm) were analyzed by aqueous size exclusion chromatography (ASEC) using an aqueous eluent of 20%/80% acetonitrile/0.05 M Na2SO4(aq). A flow rate of 0.3 mL/min, TOSOH Biosciences TSK-GEL columns (G3000 PWXL,
